Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma

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This randomized phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as BRAFV600 and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

IV. To evaluate the activity (RECIST-defined response rate, median PFS) and safety of dabrafenib + trametinib in patients who have had disease progression on ipilimumab + nivolumab and in comparison to its activity and safety in ipilimumab + nivolumab naive patients.

V. To evaluate the activity of ipilimumab + nivolumab (RECIST-defined response rate, median PFS) and safety in patients who have had disease progression on dabrafenib + trametinib and in comparison to its activity and safety in dabrafenib + trametinib naive patients.

VI. To assess the feasibility of crossover to the alternative treatment strategy (percentage of patients who are able to crossover from one arm to the other and complete at least an initial course [12 weeks] of treatment after cross-over without intervening symptomatic disease progression or treatment limiting toxicity).

Ia. To determine the association of inherited genetic variation and immune-associated adverse events in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines, cytokine receptors and within the major histocompatibility complex (MHC) region and an agnostic genome-wide single nucleotide polymorphism (SNP)-based approach.

Ib. To investigate the association between inherited genetics and survival in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines profile, cytokine receptors and within the MHC region and an agnostic genome-wide SNP-based approach.

Ic. To replicate genomic markers identified in the above aims in an independent sample set of patients treated with ipilimumab containing regimens and preliminarily characterize their potential functional role by completing replication of variation as associated with immune-related adverse events (irAEs) and survival and bio-informatic assessment of genomic markers.

II. To determine the utility of circulating BRAF levels in determining the response and resistance to either BRAF/MEK directed and/or combination immunotherapy in patients with BRAF mutant melanoma.

IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.

OUTLINE: Patients are randomized to 1 of 2 treatment arms (Arm A or Arm B).

ARM A:

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab intravenously (IV) over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C.

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C.

Biological: Ipilimumab

Given IV

Other Names:

Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody

BMS-734016

MDX-010

MDX-CTLA4

Yervoy

Biological: Nivolumab

Given IV

Other Names:

BMS-936558

MDX-1106

NIVO

ONO-4538

Opdivo

Other: Quality-of-Life Assessment

Ancillary studies

Other Name: Quality of Life Assessment

Experimental: Arm B (BRAF inhibitor therapy)

Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm D.

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Overall survival (OS) rate [ Time Frame: The time from randomization to death from any cause, assessed for up to 2 years ]

Defined as the proportion of patients alive after 2 years of follow-up time. Will be estimated and compared between the two arms using the Mantel-Haenszel test based (stratified by Eastern Cooperative Oncology Group [ECOG] performance status [PS] and lactate dehydrogenase [LDH]) based on two-sided overall type I error rate of 0.05 adjusting for two-interim analysis. Mantel-Haenszel test will compare the 2-year OS rates while controlling for the stratification factors. The difference in 2-year OS rates in arms A and B will be estimated and presented with 95% repeated confidence interval of Jennison-Turnbull. In addition, OS distribution will be estimated using the Kaplan-Meier method. The distribution of OS will be compared using the stratified log rank test. Hazard of OS will be estimated as a function of time in arm A and in arm B (as randomized in step 1 to arm A versus B) and presented graphically.

Secondary Outcome Measures :

Progression-free survival (PFS) [ Time Frame: The time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years ]

Evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Distribution will be estimated using the Kaplan-Meier method. PFS will be compared using the log-rank test.

Response rate [ Time Frame: Up to 5 years ]

According to RECIST 1.1. Response rates will be compared using the Mantel-Haenszel test (stratified by ECOG PS and LDH) test in arms A vs. B. Response rate for patients who are treated with ipilimumab/nivolumab before crossover (arm A) vs. for patients who were initially treated with dabrafenib/trametinib and crossed over to ipilimumab/nivolumab will be compared (arm D). Response rates will be compared using the Fisher's exact test.

Toxicity rate for individual adverse events (AEs) [ Time Frame: Up to 5 years ]

Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.

Toxicity rate for categorized AEs [ Time Frame: Up to 5 years ]

Will be assessed using CTCAE v 4.0. Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.

Toxicity rate for worst degree AEs [ Time Frame: Up to 5 years ]

Will be assessed using CTCAE v 4.0. Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.

Other Outcome Measures:

Genetic characteristics [ Time Frame: Baseline ]

Genetic associations with immune-related adverse events (irAE) status will be assessed using Fisher's exact test, one-degree-of-freedom genotypic trend test or the two-degrees-of-freedom chi-squared test of independence at each individual SNP marker. Tests of association will be adjusted for age, sex, center or clinical protocol, and dose as well as American Joint Committee on Cancer stage, ulceration, performance status, LDH level, number of involved sites, BRAF mutation status (when available) and number of prior therapies using logistic regression modeling assuming an additive genetic model.

Immune-related adverse events (irAE) status [ Time Frame: Up to 2 years ]

Genetic associations with irAE status will be assessed using Fisher's exact test, one-degree-of-freedom genotypic trend test or the two-degrees-of-freedom chi-squared test of independence at each individual SNP marker. Tests of association will be adjusted for age, sex, center or clinical protocol, and dose as well as American Joint Committee on Cancer stage, ulceration, performance status, LDH level, number of involved sites, BRAF mutation status (when available) and number of prior therapies using logistic regression modeling assuming an additive genetic model.

Quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWIST) [ Time Frame: Up to 2 years ]

The restricted mean amount of time for each health state will be estimated using the Kaplan-Meier method, with time limit set at 2 years for computation of all restricted means. The mean amount of time for each health state and the average group utility scores will be summarized by initial treatment (i.e., arm A: ipilimumab + nivolumab [with subsequent dabrafenib + trametinib] vs. arm B: dabrafenib + trametinib [with subsequent ipilimumab + nivolumab]). The Q-TWiST subscore and the overall Q-TWiST score will then be reported by initial treatment. Differences between treatment groups in the mean Q-TWiST score (including the overall score and the subscore) will be calculated. For each score, a 95% confidence interval and two-sided P-value for testing the null hypothesis of no difference between treatment groups will be conducted using a Z-test (with normal approximation), with standard errors calculated by the bootstrap method.

Overall function [ Time Frame: Up to 24 months from study entry ]

Assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) PROFILE-29. A log-normal survival model for analyzing longitudinal data which incorporates the non-ignorable censoring mechanism will be fitted for each short form T-score and pain intensity, separately, to assess initial treatment effect (i.e., arm A: ipilimumab + nivolumab [with subsequent dabrafenib + trametinib] vs. arm B: dabrafenib + trametinib [with subsequent ipilimumab + nivolumab]) on each function. To evaluate the effect of treatment sequence on patient function, each of the PROMIS short form T-score and pain intensity (with longitudinal data collected at baseline, 6-, 12-weeks, and 6-months after the initiation of treatment in each step) will be compared by treatment sequence for ipilimumab + nivolumab (arm A vs. D) and for dabrafenib + trametinib (arm B vs. C), using a log-normal survival model as described above.

Change in patient-reported symptoms [ Time Frame: Baseline to up to 6 months after the initiation of treatment in each step ]

Assessed using the Patient Reported Outcomes Common Terminology Criteria for Adverse Events. To evaluate the effect of treatment sequence on symptoms, summary statistics (frequency [N] and percentage [%]) will be reported with respect to presence, frequency and severity (if applicable) for each symptom by treatment sequence for ipilimumab + nivolumab (arm A vs. D), and for dabrafenib + trametinib (arm B vs. C) at baseline, 6-, 12-weeks, and 6-months after the initiation of the first treatment and the secondary treatment.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

STEP 1

Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1

The effects of dabrafenib and trametinib or ipilimumab and nivolumab on the developing human fetus are unknown; furthermore, dabrafenib has been reported to interfere with the effect of hormone based oral contraceptives; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and sexually active males must agree to use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; women of child-bearing potential must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 5 months after the last dose of nivolumab and/or ipilimumab and sexually active males must use at least two other accepted and effective methods of contraception and/or abstain from sexual intercourse for at least 7 months after the last dose of nivolumab and/or ipilimumab; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

Patients must have unresectable stage III or stage IV disease

Patients must have measurable disease; all sites of disease must be evaluated within 4 weeks prior to randomization

Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive

NOTE: Any patient with BRAF V600 mutant melanoma (whether cutaneous, acral or mucosal primary) who meets the eligibility criteria is eligible for participation in this trial; patients with uveal melanoma are not eligible for this trial

Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor; also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease

Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting >= 4 weeks prior to entering the study and recovered from adverse events due to those agents; mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study; patients must have discontinued radiation therapy >= 1 week prior to entering the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration and patients must be fully recovered from post-surgical complications

Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert's syndrome (obtained within 4 weeks prior to randomization)

Individuals who are known to be human immunodeficiency virus (HIV) infected are eligible (note: HIV testing is not required for entry into the study)

STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): The patient must have met all eligibility criteria (except as detailed below) at the time of crossover

RECIST defined measurable disease is not required

Only prior systemic therapy as part of step 1 is allowed; patients who received allowed systemic therapy in the adjuvant setting prior to Step 1 and were eligible for Step 1 are not excluded from proceeding to Step 2 if they meet other eligibility criteria

Malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to ipilimumab + nivolumab treatment

History of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib therapy

Patients crossing over from nivolumab/ipilimumab to dabrafenib/trametinib who underwent surgery or SRS to CNS metastases need not be off of steroids to start treatment

There is no restriction on serum lactate dehydrogenase (LDH) at crossover

Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study principal investigator (PI) at time of crossover

STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients must have melanoma that is metastatic and clearly progressive on prior therapy

STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients must be at least 1 week from documented progressive disease (PD) on Step 1 of current study; all sites of disease must be evaluated within 4 weeks prior to registration

STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy; patients with immune related toxicities from ipilimumab + nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less

STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients must have discontinued radiation therapy prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications

The effects of dabrafenib and trametinib or ipilimumab and nivolumab on the developing human fetus are unknown; furthermore, dabrafenib has been reported to interfere with the effect of hormone based oral contraceptives; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and sexually active males must agree to continue to use the same contraception requirements as on Step 1 of this study (i.e. use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; women of child-bearing potential must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 5 months after the last dose of nivolumab and/or ipilimumab and sexually active males must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 7 months after the last dose of nivolumab and/or ipilimumab); should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

Exclusion Criteria:

Women must not be pregnant or breast-feeding, as the effects of ipilimumab + nivolumab or dabrafenib + trametinib on the developing human fetus are unknown

All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Patients must not receive any other investigational agents while on study or within four weeks prior to registration

Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible; patients must not have taken any steroids =< 10 days prior to randomization for the purpose of managing their brain metastases; repeat imaging after SRS or surgical resection is not required so long as baseline magnetic resonance imaging (MRI) is within 4 weeks of registration; patients with multiple brain metastases treated with SRS (with [w] or without [w/o] whole-brain radiotherapy [WBRT]), are not an exclusion; patients with definitive CNS metastases treated with only WBRT are ineligible; patients with potential CNS metastases that are too small for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain etiology are potentially eligible, but need to be discussed with and approved by the study principal investigator (PI)

Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for > 2 years prior to the time of registration

Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, or psychiatric illness/social situations that would limit compliance with study requirements, interfere with subject's safety, or obtaining informed consent; therapeutic level dosing of warfarin can be used with close monitoring of prothrombin time (PT)/international normalized ratio (INR) by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency

Patients must not have a history of or evidence of cardiovascular risks including any of the following:

Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), should be evaluated for the presence of target organ involvement and potential need for systemic treatment; if no systemic immune suppression is deemed necessary they can be eligible

The following medications or non-drug therapies are also prohibited while on treatment in this study:

Other anti-cancer therapies

Other investigational drugs

Patients taking any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible

Patients must not have history of retinal vein occlusion (RVO)

Patients must not have evidence of interstitial lung disease or pneumonitis

Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib

STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE): Patients are ineligible if they have any currently active CNS metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible to proceed; patients crossing over from dabrafenib/trametinib to nivolumab (nivo)/ipilimumab (ipi) must not have taken any steroids =< 10 days prior to registration for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases are ineligible; patients with definitive CNS metastases treated with only WBRT are ineligible; patients with potential CNS metastases that are too small for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain etiology are potentially eligible, but need to be discussed with and approved by th